The long-term objective of the proposed research is to enhance our understanding of pain mechanisms and their control in the dorsal horn of the medulla (trigeminal nucleus caudalis), a region closely associated with many clinical pain conditions such as migraine, toothache, trigeminal neuralgia and temporomandibular joint related disorders. Specifically, the proposed research will elucidate the sex-related differences in the control ofnociceptive information originating from oro-facial tissues particularly the tooth pulp. The specific aims of the investigation are to determine that, a) activation of alpha2-adrenoceptors (alpha2-ARs) and descending noradrenergic pathway from the Kolliker Fuse nucleus (KF = A7) produce sex-specific modulation of trigeminal nociception through the participation of gonadal steroids, and b) the sex-specific modulation is mediated by gonadal hormone-induced, particularly estrogen-induced, genomic and non-genomic mechanisms The proposed studies will be carried out using electrophysiological, behavioral, molecular (in-situ hybridization) and cellular (in-vitro intracellular) techniques in male, proestrous female, ovariectomized, estradiol treated ovariectomized females, castrated males, testosterone treated castrated males and sham operated animals. Single unit activity of tooth pulp specific (TPS), nociceptive specific (NS) and wide dynamic range (WDR) neurons including trigeminothalamic neurons will be recorded in the superficial and deeper dorsal horn of the medulla in anesthetized male and female rats. Effects of microiontophoretically applied alpha2-AR agonists and antagonists will be tested on the responses evoked by, a) electrical stimulation of the tooth pulp, b) noxious stimuli, and c) activation of N-methyl-D-aspartic acid (NMDA) receptors. Nociceptive scratching behavior will be elicited by microinjection of NMDA through a cannula implanted dorsal to the medullary dorsal horn. Effects of alpha2-AR agonists and antagonists microinjected through the same cannula, and stimulation in KF will be investigated on the NMDA-induced nociceptive scratching behavior in males and females. Contribution of gonadal steroid-induced genomic and non-genomic changes in generating sex-related differences will be investigated by examining whether, a) estrogen and testosterone alter the expression of the alpha2A-AR gone in the dorsal horn of the medulla, b) the estrogen receptor is co-localized in alpha2A-AR containing neurons, and c) estrogen alters the coupling of alpha2-ARs to potassium channels. The proposed studies will deepen our understanding of sex-related differences in the modulation of trigeminal nociception and lead to the development of better pain control strategies in males and females. The new information may also help in the development of analgesics that are free of the abuse potential and side effects associated with narcotics such as morphine.